Premium
Endothelial HIF‐1α Is Required for Endothelial Regeneration and Vascular Repair Following Sepsis Challenge
Author(s) -
Huang Xiaojia,
Zhang Xianmin,
Zhao Youyang
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1065.6
Subject(s) - vascular endothelial growth factor b , endothelial activation , regeneration (biology) , endothelial stem cell , inflammation , sepsis , vascular endothelial growth factor , endothelial dysfunction , vascular endothelial growth factor c , hypoxia (environmental) , microbiology and biotechnology , vascular endothelial growth factor a , endothelium , biology , cancer research , immunology , medicine , endocrinology , chemistry , vegf receptors , biochemistry , in vitro , organic chemistry , oxygen
Background Endothelial repair is critical for the maintenance of vascular homeostasis after inflammatory injury. However, little is known about the intrinsic pathways that trigger endothelial regeneration and inflammation resolution. Methods and Results Employing the mice with Tie2Cre‐mediated disruption of HIF‐1α (encoding hypoxia inducible factor 1, HIF‐1α) ( Hif1α Tie2 ) in endothelial cells, we demonstrated that endothelial regeneration requires activation of HIF‐1 α signaling in endothelial cells, which subsequently regulates the expression of the reparative transcription factor Forkhead box M1 (FoxM1). Hif1α Tie2 mice exhibited impaired vascular repair, persistent lung inflammation, and increased mortality rate after sepsis challenge. Selective restoration of either HIF‐1α or FoxM1 in pulmonary vascular endothelial cells in HIF1α Tie2 mice restored endothelial proliferation and reversed the defective vascular repair. Activation of HIF‐1α via a pharmacological approach potentiated endothelial regeneration and vascular repair. Conclusions These studies defined a critical role of endothelial HIF‐1α in activating the intrinsic FoxM1‐dependent endothelial regeneration program following inflammatory vascular injury. Thus, activation of HIF‐1α‐mediated endothelial regeneration is a promising strategy for treatment of inflammatory vascular diseases such as acute respiratory distress syndrome. Support or Funding Information This work was supported by NIH grants R01HL123957, R01HL125350.